SUMMARYA non-cognate mechanism of protection against human immunode®ciency virus-1 (HIV-1) infection involves up-regulation of b-chemokines, which bind and may down-modulate the CCR5 co-receptors, thereby preventing transmission of M-tropic HIV-1. The objective of this investigation was to evaluate this mechanism in vivo in non-human primates. Rhesus macaques were immunized by a modi®ed targeted lymph nodes (TLN) route with recombinant simian immunode®ciency virus (SIV) glycoprotein 120 (gp120) and p27 in alum, and adsorbed recombinant granulocyte± macrophage colony-stimulating factor (GM-CSF) with either interleukin (IL)-2 or IL-4. Immunization induced signi®cant increases in the concentrations of CD8 cell-derived suppressor factor (CD8-SF), regulated on activation normal T cells expressed and secreted (RANTES), macrophage in¯ammatory protein (MIP)-1a and MIP-1b, and down-modulation of the proportion of cells expressing CCR5 (r=0 . 737, P<0 . 05). The macaques were then challenged with SIVmac 220 by the rectal mucosal route. The plasma SIVmac RNA showed a signi®cant inverse correlation with the CD8-SF or the concentration of the three b-chemokines (r=0 . 831 and 0 . 824, P<0 . 01), but a positive correlation between the proportion of CCR5 + cells and SIVmac RNA (r=0 . 613, P=0 . 05). These results demonstrate for the ®rst time in vivo that immunization up-regulates b-chemokines, which may down-modulate CCR5 co-receptors, and both functions are signi®cantly correlated with the viral load. Hence, the non-cognate b-chemokine±CCR5 mechanism should be considered as complementary to speci®c immunity in vaccination against HIV.